Abstract:

DESCRIPTION (provided by applicant): HIV/AIDS is a global epidemic afflicting more than 33 million people worldwide. HIV can often be suppressed for many years with anti-retroviral medications, and over 15 billion dollars were spent on these medications in2010. Biologics such as HIV-1 neutralizing antibodies (NAbs) VRC01, PG9, and b12 and peptides such as Enfuvirtide are potent inhibitors of HIV and offer themselves as alternatives to standard small-molecule anti- retroviral medications, typically with fewer side effects. However, unlike small-molecule treatments, biologics typically have to be injected, and this need for injection can be problematic especially if the injections are frequent. For example, Enfuvirtide, the first FDA-approved biologic approved for treating HIV, requires twice- daily injections, and very frequently causes injection site reactions. Immusoft's proof-of-concept studies have demonstrated the ability to induce secretion of broadly neutralizing anti-HIV antibodies from autologous human cell with a lentiviral vector. This treatment approach eliminates the need for frequent and often painful injections. It also offers the possibility of targeting the therapeutic biologic to certain tissues harboring cells with latent HIV infection. Theproposed study will achieve three mission goals for continuing to validate the commercial viability of the delivery system in vivo. Our first specific aim will define vector and culture media requirements necessary to most efficiently transduce and expandmodified immune cells. Our second specific aim will test for compatibility of the vector, and culture system with cells from the primate Macaca nemestrina in preparation for a phase II application. Our third specific aim will introduce modified cells intoan immunocompromised mouse to measure secretion of the HIV-neutralizing antibody VRC01. Overall, the goal of these experiments is to optimize the culture system conditions, and to estimate the numbers of cells required for a phase II study in a primate model. The phase II application will investigate long-term biologic production, cell homing, and system safety in vivo, as well as expand the number of HIV-targeting biologics to those that have shown the most promise in clinical trials. Given the very high-level conservation between human and monkey biology, we expect that the critical components comprising the system will translate well. In the event that it is not possible to utilize monkey cells, we intend to utilize humanized mice, for which we have ongoing collaborations. PUBLIC HEALTH RELEVANCE: HIV is an incurable disease and a global epidemic affecting over 33.3 million people. New biologic-based treatments like monoclonal antibodies and peptides are a promising new approach with fewer side effects, but they require frequent injections. Technology that would make a patient's own cells produce biologic-based treatments constantly could be an ideal treatment strategy for HIV.